title: scAAV9 intracisternal delivery results in efficient gene transfer to the central nervous system of a feline model of motor neuron disease.
abstract: On the basis of previous studies suggesting that vascular endothelial growth factor (VEGF) could protect motor neurons from degeneration, adeno-associated virus vectors (serotypes 1 and 9) encoding VEGF (AAV.vegf) were administered in a limb-expression 1 (LIX1)-deficient cat-a large animal model of lower motor neuron disease-using three different delivery routes to the central nervous system. AAV.vegf vectors were injected into the motor cortex via intracerebral administration, into the cisterna magna, or intravenously in young adult cats. Intracerebral injections resulted in detectable transgene DNA and transcripts throughout the spinal cord, confirming anterograde transport of AAV via the corticospinal pathway. However, such strategy led to low levels of VEGF expression in the spinal cord. Similar AAV doses injected intravenously resulted also in poor spinal cord transduction. In contrast, intracisternal delivery of AAV exhibited long-term transduction and high levels of VEGF expression in the entire spinal cord, yet with no detectable therapeutic clinical benefit in LIX1-deficient animals. Altogether, we demonstrate (i) that intracisternal delivery is an effective AAV delivery route resulting in high transduction of the entire spinal cord, associated with little to no off-target gene expression, and (ii) that in a LIX1-deficient cat model, however, VEGF expressed at high levels in the spinal cord has no beneficial impact on the disease course.
authors.affiliation: INSERM UMR1089, Institut de Recherche Thérapeutique 1, Université de Nantes, 44007 Nantes Cedex 01, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bucher
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Colle
authors.forename: Erin
authors.initials: E
authors.lastname: Wakeling
authors.forename: Laurence
authors.initials: L
authors.lastname: Dubreil
authors.forename: John
authors.initials: J
authors.lastname: Fyfe
authors.forename: Delphine
authors.initials: D
authors.lastname: Briot-Nivard
authors.forename: Maud
authors.initials: M
authors.lastname: Maquigneau
authors.forename: Sylvie
authors.initials: S
authors.lastname: Raoul
authors.forename: Yan
authors.initials: Y
authors.lastname: Cherel
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Astord
authors.forename: Sandra
authors.initials: S
authors.lastname: Duque
authors.forename: Thibaut
authors.initials: T
authors.lastname: Marais
authors.forename: Thomas
authors.initials: T
authors.lastname: Voit
authors.forename: Philippe
authors.initials: P
authors.lastname: Moullier
authors.forename: Martine
authors.initials: M
authors.lastname: Barkats
authors.forename: Béatrice
authors.initials: B
authors.lastname: Joussemet
mesh_terms: D061605:Administration, Intravenous; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002415:Cats; D002946:Cisterna Magna / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D000229:Dependovirus / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D009044:Motor Cortex / Q000378:metabolism; D016472:Motor Neuron Disease / Q000628:therapy*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000378:metabolism; D014161:Transduction, Genetic; D019076:Transgenes / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D042461:Vascular Endothelial Growth Factor A; D049452:Green Fluorescent Proteins